5-oxo-1,2,3,4-tetrahydro-5h-(1)benzopyrano(3,4-d)pyridines



United States Patent Olhce US. or. 260-295 4 Claims ABSTRACT OF THEDISCLOSURE New 8-alkyl- (and 8-cycloalkyl-lower-alkyl-) 10-hydroxy 5 oxo1,2,3,4 tetrahydro 5H [1]benzopyrano[3,4-d]pyridines and 10-alkyl- (and10-cycloalkyllower-alkyl 8 hydroxy 5 OX 1,2,3,4 tetrahydro- H[1]benzopyrano[3,4 d] pyridine useful as intermediates for preparing8-alkyland 8-cycloalkyl-loweralky1-), 5,5 di lower alkyl hydroxy 1,2,3,4tetrahydro 5H [l]benzopyrauo[3,4 d]pyridines and l 0-alkyl- (and10-cycloalkyl-lower-alkyl-) 5,5-di-1oweralkyl 8 hydroxy 1,2,3,4tetrahydro 5H [1]benzopyrano[3,4-d]pyridines are prepared by reaction ofa 4- carbo-lower-alkoxy-3-piperidone with a 5-alkylresorcinol (or a5-cycloalkyl-lower-alkylresorcinol) oxo 1,2,3,4 tetrahydro 5H[1]benzopyrano[3, 4 d] pyridines and IO-alkyl- (and10-cycloalky]-lower-alkyl-) 8 hydroxy 5 oxo 1,2,3,4 tetrahydro 5H [1]benzopyrano [3 ,4-d] pyridines.

Without limiting the generality of the foregoing, illustrative andpreferred embodiments of our 8-alky1- (and 8 cycloalkyl lower alkyl-)10' hydroxy 5 oxo- 1,2,3,4 tetrahydro 5H [1]benzopyrano[3,4 d] pyridincsand IO-alkyl- (and lo cycloalkyl-lower-alkyl-) 8 hydroxy 5 oxo 1,2,3,4tetrahydro 5H [1] benzopyrano[3,4-d]pyridines are those of Formula I:

wherein one of X and X is hydroxy (H0) and the other is R R is a memberof the group consisting of alkyl and cyclo-alkyl-lower-alkyl; and R is amember of the group consisting of hydrogen, cycloalkyl-lower-alkyl,lower-alkenyl, lower-alkylnyl, halo-lower-alkenyl (including fluoro-,chloro-, bromo-, and iodo-lower-alkenyl), phenyl-lower-alkyl,phenyl-lower-alkenyl, and phenyllower-alkynyl.

Patented Oct. 20, 1970 As used herein, the term lower-alkyl meanssaturated monovalent aliphatic radicals, including straight andbranched-chain radicals, of from one to six carbon atoms, as illustratedby, but not limited to methyl, ethyl, propyl, isopropyl, butyl,sec.-butyl, amyl, or hexyl.

As used herein, the term alkyl means saturated, monovalent aliphaticradicals, including straight and branchedchain radicals, of from one totwenty carbon atoms, as illustrated by, but not limited to methyl,n-amyl, n-hexyl, 2-heptyl, n-heptyl, 3-methyl-2-octyl, n-octyl, 2-nonyl,2- tetradecyl, n-hexadecyl, or 2-eicosanyl.

As used herein, the term lower-alkenyl means monovalent, aliphaticradicals of from three to seven carbon atoms which contain at least onedouble bond, and are either straight or branched-chain, as illustratedby, but not limited to l-(2-propenyl), 1-(3-n1ethyl-2-propenyl), l-(1,3-dimethyl-2-propenyl), or 1-(2-hexenyl).

As used herein, the term lower-alkylny means monovalent, alphaticradicals of from three to seven carbon atoms 'which contain at least onetriple bond, and are either straight or branched, as illustrated by, butnot limited to I-(Z-propynyl), l-(l-methyl-Z-propynyl), or 1-(Z-heptynyl) As used herein, the term cycloalkyl means cyclic, saturatedaliphatic radicals of from three to eight ring carbon atoms, asillustrated by, but not limited to cyclopropyl, cyclobutyl,Z-methylcyclobutyl, cyclohexyl, 4- methylcyclohexyl, or cyclooctyl.

As used herein, the terms phenyl-lower-alky "phenyl-lower-alkenyl, andphenyl-lower-alkynyl mean monovalent radicals consisting of a phenylnucleus bonded to the rest of the molecule through, respectively, adivalent lower-alkylene radical of from one to four carbon atoms, asillustrated by, but not limited to methylene, 1,l-ethylene,1,2-ethylene, 1,3-propylene, 1,2-propylene, or 1,4-butylene; or througha divalent lower-alkenylene radical of from two to four carbon atoms, asillustrated by, but not limited to 1,2-ethenylcne, 1,3-( l-propenylene),1,3-(1-butenylene), or 1,4-(2-butenylene); or through a divalent lower-alkynylene radical of from two to four carbon atoms, as illustratedby, but not limited to 1,2- ethynylene,1,3propynylene,l,3-(l-butynylene), and the like. Moreover the benzenering of such phenyl-lower- 'alkyl, phenyl-lower-alkenyl, andphenyl-lower-alkynyl radicals can be substituted by one or moresubstituents selected from the group consisting of lower-alkyl,loweralkoxy, halo (chloro, bromo, iodo, or fluoro), nitro,loiweralkylmercapto, mcthylenedioxy, and trifluoromethyl.

The compounds of Formula I above Where R is benzyl are advantageouslyprepared by reacting a l-benzyl-4- carbo-lower-alkoxy-3-piperid0ne ofFormula ]I with a 5- alkylresorcinol (or a5-cyclo-alkyl-lower-alkylresorcinol) of Formula III. The reaction iscarried out in a mixture of concentrated sulfuric acid and phosphorusoxychloride or in the presence of other condensation agents such asaluminum chloride, hydrogen chloride, or polyphosphoric acid and isillustrated by the equation:

COO-Alk where R R X and X are defined as above. As indicated above, thecyclization of the 1-benzy1-4-carbolower-alkoxy-3-piperidone of FormulaII takes place at either the 2-position of the S-alkyl-resorcinol (togive the compounds of Formula I where X is hydroxy and X is R or at the4-position of the latter (to give the compounds of Formula I where X ishydroxy and X is R The compounds of Formula I where R is hydrogen areadvantageously prepared by catalytic debenzylation of the correspondingcompounds where R is benzyl. The reaction is preferably carried out inan organic solvent inert under the conditions of the reaction, forexample methanol, ethanol, or isopropanol. Suitable catalysts areplatinum or palladium-on-charcoal. A preferred catalyst ispalladium-on-charcoal.

The compounds of Formula I where R is cycloalkyllower-alkyl,lower-alkenyl, lower-alkynyl, halo-loweralkenyl, phenyl lower alkyl,phenyl-lower-alkenyl, or phenyl lower alkynyl are advantageouslyprepared by reaction, in the presence of an acid acceptor, of thecorresponding compounds where R is hydrogen with an appropriatecycloalkyl-lower-alkyl halide, lower-alkenyl halide, lower-alkynylhalide, halo-lower-alkenyl halide, phenyl-lower-alkyl halide,phenyl-lower-alkenyl halide, or phenyl-lower-alkynyl halide.

The reaction is preferably carried out in an organic solvent inert underthe conditions of the reaction, for example methanol, ethanol,isopropanol, or dimethylformamide, and in the presence of anacid-acceptor. The purpose of the acid-acceptor is to take up thehydrogen halide split out during the course of the reaction and is abasic substance which forms water-soluble salts readily separable fromthe reaction mixture. Suitable acidacceptors are alkali metal carbonatesor bicarbonates, for example sodium or potassium carbonate, orbicarbonate, or alkali metal hydroxides, for example sodium or potassiumhydroxide. The reaction can also be carried out in the presence of amolar excess of the base of Formula I where R is hydrogen. A preferredacid-acceptor is sodium carbonate, and a preferred solvent is ethanol.

The intermediate S-alkylor -cycloa1kyl-lower-alkylresorcinols of FormulaIII are conveniently prepared by methods generally known in the artcomprising dehydration of a 3,S-di-lower-alkoxyphenyl alkyl (orcycloalkyllower-alkyl) carbinol, reduction of the resulting 3,5-diloweralkaxyphenylalkene (or di-lower-alkoxyphenylcycloalkyl-lower-alkene),and hydriodic acid cleavage of the ether groups to the corresponding5-alkyl- (or 5- cycloalkyl-lower-alkyl-) resorcinol. The startingcarbinols in turn are prepared by reaction of an appropriate Grignardreagent with a 3,5-di-lower-alkoxybenzoic acid ester, amide, or 3,5-dilower-a1koxy-alkanophenone (or 3,5'-di-lower-alkoxy-cyclo-alkyl-lower-alkanophenone).

The intermediate l-benzyl 4 carbo-lower-alkoxy-3- piperidones of FormulaII are prepared by the method of Prill and McElvain, J. Am. Chem. Soc.,55, 1233 (1933) and of McElvain and Vozza, I. Am. Chem. Soc., 71, 896(1948).

The compounds of Formula I as described hereinabove are used asintermediates for the preparation of S-alkyl- (or8-cycloalkyl-lower-alkyl-) 5,5di-loweralkyl-10-hydroxy-1,2,3,4-tetrahydro 5H [l]benzopyrano[3,4-d]-pyridines and -alkyl- (and 10-cycloalkyl-lower-alkyl-)5,5-di-lower-alkyl 8 hydroxy-l,2,3,4-tetrahydro-5H- [l]benzopyrano[3,4-d]pyridines of Formula IV:

Ra where R R X and X have the meanings given above, and R representslower-alkyl. The compounds of Formula lV where X is hydroxy and X is Rare disclosed and claimed in our copending application, Ser. No.490,687, filed Sept. 27, 1965.

The compounds of Formula IV are prepared by reacting an 8-alkyl- (or8-cycloalkyl-lower-alkyl-) IO-hydroxy- 5-oxo-1,2,3,4-tetrahydro 5H[1]benzopyrano[3,4-d]- pyridine or 10-alkyl- (or 10-cycloalkyl-loweralkyl-) 8- hydroxy-S-oxo-l,2,3,4-tetrahydro 5H [l] benzopyrano- [3,4-d]pyridine of the instant invention having the Formula I hereinabove witha lower-alkyl magnesium halide as illustrated by the equation:

where R R R X and X have the meanings given hereinabove, and Halrepresents halogen. The reaction is carried out in an organic solventinert under the conditions of the reaction. Suitable solvents arediethyl ether, dibutyl ether, tetrahydrofuran, anisole, pyridine, andthe like. It is preferred to add a solution of the 8-alkyl- (or8-cycloalkyl-lower-alkyl-) 10-hydroxy 5 oxo-1,2,3,4 tetrahydro 5H[l]benzopyrano[3,4-d]pyridine or 10- alkyl- (or10-cycloalkyl-lower-alkyl-) 8 hydroxy-S-oxo- 1,2,3,4-tetrahydro 5H[1]benzopyrano[3,4-d]pyridine in a pyridine or anisole solution, or in amixture of these solvents, to a solution of the Grignard reagent inanisole.

Due to the presence of a basic amino grouping, the compounds of thisinvention form acid-addition salts. The compounds of Formula I, in freebase form, are converted to the acid-addition salt form by interactionof the base with an acid. In like manner, the free bases can beregenerated from the acid-addition salt form in the conventional manner,that is by treating the salts with strong aqueous bases, for examplealkali metal hydroxides, alkali metal carbonates, and alkali metalbicarbonates. The bases thus regenerated can then be interacted with thesame or a dilferent acid to give back the same or differentacid-addition salt. Thus the novel bases and all of their acid-additionsalts are readily interconvertible. It will thus be appreciated thatFormula I not only represents the structural configuration of the basesof our invention but is also representative of the structural entitywhich is common to all if our compounds of Formula I whether in the formof the free bases or in the form of the salts of the bases.

Our salts are useful as characterizing or identifying derivatives of thefree bases or in isolation or purification procedures. Suchcharacterizing or purification acid-addition salt derivatives, like allof the acid-addition salts, can if desired, be used to regenerate thefree bases by reaction of the salts with aqueous base, or alternativelythe acid-addition salt can be converted to a different characterizing oridentifying salt by, for example, ion-exchange procedures. Thereforealthough insolubility or lack of crystalline character may make someparticular salt species unsuitable or less desirable for use as such ina given identification or purification procedure, such salts can beconverted to the free base by decomposition of the acid-addition saltwith aqueous base as explained above, or alternatively, theacid-addition salt can be converted to a more suitable salt species bydouble decomposition reactions involving the anion, for example, byion-exchange procedures.

It will be appreciated from the foregoing that all of the acid-additionsalts of our new bases are useful and valuable compounds regardless ofconsiderations of solubility, physical form, and the like, andaccordingly are within the purview of the instant invention.

The novel features of the compounds of the invention, then, reside inthe concept of the bases and the cationic forms of the new compounds ofFormula I and not in any particular acid moiety or anion associated withthe salt forms of the compounds; rather, the acid moieties or anionswhich can be associated in the salt forms are in themselves neithernovel nor critical and therefore can be any anion or acid-like substancecapable of salt forma tion with bases. In fact, in aqueous solutions,the base form or water-soluble of acid-addition salt form of thecompounds of the invention both possess a common protonated cation orammonium ion.

Thus appropriate acid-addition salts are those derived from such diverseacids as formic acid, acetic acid, isobutyric acid,alpha-mercaptopropionic acid, malic acid, fumaric acid, succinic acid,succinamic acid, tartaric acid, citric acid, lactic acid, benzoic acid,4-methoxybenzoic acid, phthalic acid, anthranilic acid,l-naphthalenecarboxylic acid, cinnamic acid, cyclohexane-carboxylicacid, mandelic acid, tropic acid, crotonic acid, acetylene dicarboxylicacid,'sorbic acid, 2 furancarboxylic acid, cholic acid, pyrenecarboxylicacid, 2 pyridinecarboxylic acid, 3indoleacetic acid, quinic acid,sulfamic acid, methanesulfonic acid, isethionic acid, benezenesulfonicacid, p-toluenesulfonic acid, benzenesulfinic acid, butylarsonic acid,diethylphosphinic acid, p-aminophenylarsinic acid, phenylstibnic acid,phenylphosphinous acid, methylphosphinic acid, phenylphosphinic acid,hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid,perchloric acid, nitric acid, sulfuric acid, phosphoric acid,hydrocyanic acid, phosphotungstic acid, molybdic acid, phosphomolybdicacid, pyrophosphoric acid, arsenic acid, picric acid, picrolonic acid,barbituric acid, or boron trifluoride.

The acid-addition salts are prepared either by dissolving the free basein an aqueous solution containing the appropriate acid and isolating thesalt by evaporating the solution, or by reacting the free base and acidin an organic solvent, in which case the salt separates directly or canbe obtained by concentration of the solution.

The compounds of Formula IV, which are disclosed and claimed in parentapplication Ser. No. 490,687, have been shown to possess central nervoussystem depressant activity as evidenced by gross overt changes inducedby intravenous administration in mice in standard tests as described byIrwin in Animal and Clinical Pharmacologic Techniques in Drug Evaluation(edited by Nodine and Siegler), Year Book Medical Publishers, Inc.,Chicago, 111., pp 36-54 (1964), which tests involve observations ofpsychomotor activity, reactivity to stimuli, and ability to performnormal, non-conditioned motor tasks. This activity indicates theusefulness of the compounds of Formula IV as psychotropic agents.

The molecular structures of the compounds of our invention were assignedon the basis of study of their infrared, ultraviolet, and NMR spectraand their transformation products, and conformed by the correspondencebetween calculated and found values for the elementary analyses forrepresentative examples.

The following examples will further illustrate the invention without,however, limiting it thereto.

EXAMPLE 1 2 benzyl-lO-hydroxy-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-

tetrahydro-5H-[ 1]benzopyrano[3,4 d] pyridinehydro chloride To a mixtureof 5.4 g. (0.023 mole) of 5-(3-methyl- 2-octyl)resorcinol and 5.8 (0.020mole) of N-benzyl-4- carbethoxy-3-piperidone [prepared according to thepro cedure of Iselin et al., Helv. Chim. Acta, 37, 178-184 (1954) andMcElvain et al., J. Am. Chem. Soc, 71, 896- 900, 1948)] was addeddropwise with cooling 10.5 ml. of concentrated sulfuric acid. Themixture was then treated all at once with 3 ml. of phosphorusoxychloride, stirred at room temperature for twenty-four hours and thenpoured into an excess of aqueous sodium bicarbonate. The gum whichseparated was taken into chloroform, and the organic solution was washedfirst with aqueous sodium bicarbonate, then with water, and dried, firstby azeotropic distillation, and then over anhydrous sodium sulfate.. Thechloroform solution was taken to dryness, and the residue extracted withacetonitrile and filtered. The combined filtrates were evaporated todryness giving a dark, viscous gum which was dissolved in ethyl acetateand treated with a solution of concentrated hydrochloric acid in ethylacetate. The solid which separated was collected, washed with ethylacetate, and dried to give 2.3 g. of 2-benzyl-10-hydroxy-8-(3-methyl-2-octyl) 5 oxo-1,2,3,4-tetrahydro-SH-[1]benzopyrano[3, 4-d] pyridinehydrochloride, M.P. 217222 C. (dec.). (The free base melts at 137138 C.)

The latter was converted to 2-benzyl-5,5-dimethyl-10- hydroxy 8(3-methyl-2-octyl)-1,2,3,-tetrahydr0-5H-[l] benzopyrano[3,4-d] pyridineas follows:

The above described 2-benzyl-10-hydroxy-8-(3-methyl- 2 octyl) 5oxo-1,2,3,4-tetrahydro-5H-[1]benzopyrano [3,4-d1pyridine (4.3 g., 0.01mole), in the form of the free base, was dissolved in 30 ml. of dryanisole, and the solution added dropwise to a solution containing 0.1mole of freshly prepared methyl magnesium iodide in 50 m1. of anisole.The solution was stirred overnight at 50 C., cooled, and the excessGrignard reagent decomposed with 50 ml. of water. The solution wasacidified with ml. of 4 N sulfuric acid, the anisole was steam distilledfrom the mixture, and the residual solution was basified with solidsodium carbonate and filtered. Extraction of the solid filter with coldacetonitrile, filteration of the extracts, and evaporation of the latterto dryness afforded 5.2 g. of a mossygreen solid, M.P. 92112 C., whichwas further extracted with ether leaving 2.4 g. of a light blue solid,M.P. 197-200 C. as the hydriodide salt. Recrystallization from a mixtureof ether and ethyl acetate raised the melting point to 202205 C.

Analysis.Calcd. for C H INO (percent): C, 62.60; H, 7.35; N, 2.43. Found(percent): C, 62.46; H. 7.24; N, 2.67.

The salt can be converted to the free base by dissolving in chloroformand shaking with aqueous sodium bicarbonate. The free base precipitatedfrom solution and remained suspended in the chloroform layer. The basewas filtered off, washed with water and finally with chloroform. Theproduct was recrystallized from acetonitrile to give colorless crystals,M.P. 202204 C.

EXAMPLE 2 2-benzyl-10-hydroxy-8-methyl-5-oxo-1,2,3,4-tetrahydro- 5H-[ 1Jbenzopyrano 3,4-d] pyridine Following a procedure similar to thatdescribed in Example 1 hereinabove, N-benzyl-4-carbethoxy-3-piperidoneis reacted with S-methylresorcinol to give 2 -benzyl- 10 hydroxy8-methyl-5-oxo-1,2,3,4-tetrahydro-5H-[1] benzopyrano [3,4-d] pyridine.

The latter, on reaction with methyl magnesium iodide according to theprocedure of Example 1 hereinabove, gives2-benzyl-10-hydroxy-S,5,8-trirnethyl-1,2,3,4-tetrahydro-5-H- 11benzopyrano [3,4-d] pyridine.

EXAMPLE 3 2-benzyl-l-hydroxy-S-oxo-S-( l-pentyl)-1,2,3,4-tetrahydro- SH-1 ]benzopyrano 3,4-d] pyridine Following a procedure similar to thatdescribed in Example 1 hereinabove, 5-(l-pentyl)resorcinol is reactedwith N-benzyl-4-carbethoxy-3-piperidone hydrochloride in the presence ofconcentrated sulfuric acid and phosphorus oxychloride to give a mixtureof Z-benzyl-l-hydroxy-S- oxo8-(1-pentyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano [3,4-d1pyridine, M.P.180181 C., and 2-benzyl-8-hydroxy 5oxo-10-(l-pentyl)-l,2,3,4-tetrahydro-5H-[1] benzopyrano[3,4-d]pyridine,M.P. -176" C. These were separated by extraction with dichloromethanewhich dissolved the latter isomer and precipitated the former. Theformer was recrystallized from acetonitrile to give crystals, M.P.180-181 C. The latter was recrystallized from a mixture of chloroformand petroleum ether, M.P. 175-176 C.

These two isomers were separately reacted with methyl magnesium bromideor iodide according to the procedure of Example 1 hereinabove, to give,respectively, Z-benzyl- 5,5 di methyl 1hydroxy-8-(1-pentyl)-1,2,3,4-tetrahydro H [1]benzopyrano[3,4-d]pyridine,M.P. 202- 203 C.

Analysis.Calcd for C H NO (percent): C, 79.75; H, 8.50; N, 3.58. Found(percent): C, 79.83; H, 8.47; N, 3.48, and2-benzyl-5,5-dimethyl-8-hydroxy-10-(l-pentyl) 1,2,3,4 tetrahydro 5H[1]benzopyrano[3,4-d] pyridine, M.P. 153-154 C. Analysis.Found(percent): C, 79.64; H, 8.42; N, 3.56.

EXAMPLE 4 (A) 5-(2-heptyl)resorcinol A solution of 45 g. (0.19 mole) of3,5'-dimethoxyhexanophenone in 400 ml. of dry ether was added dropwiseto a freshly prepared solution of 0.30 mole of methyl magnesium iodidein 150 ml. of ether. The mixture was heated under reflux for one hour,cooled, and carefully decomposed with 275 ml. of saturated aqueousammonium chloride. Separation of the ether layer, extraction of theaqueous phase with ether, and evaporation of the dried, combinedextracts to dryness afforded 49.4 g. of2-(3,5-dimethoxyphenyl)-2-heptanol as an oil, which was not furtherpurified.

The latter was treated with 1 ml. of sulfuric acid and heated at 105125C./35 mm. for an hour and a half. The mixture was then cooled andextracted with ether, and the ether extracts washed with aqueous sodiumbicarbonate and water, dried over sodium sulfate, and

evaporated to dryness. Distillation of the residue in vacuo gave 34.1 g.of 2-(3,5-dimethoxyphenyl)-2-heptene, B.P. 132140 C./4 mm., 11 1.5251.

The latter (33 g., 0.14 mole), dissolved in 100 ml. of absolute ethanol,was reduced with hydrogen at 1500 pounds p.s.i. over 6 g. of Raneynickel at 150 C. After removing the catalyst by filtration andevaporation of the filtrate to dryness, the residue was distilled invacuo to give 26 g. of 2-(3,4-dimethoxyphenyl)heptane, B.P. 137- 139C./1 mm., 11 1.4957.

The latter (26 g., 0.11 mole), dissolved in 118 ml. (0.9 mole) of 57%hydriodic acid, was treated carefully with 156 ml. (1.6 moles) of aceticanhydride. When the exothermic reaction had subsided, the mixture washeated in an oil bath at 155 C. for two hours, cooled, and poured into amixture of ice and water. The mixture was stored in a refrigeratorovernight, and the gummy semisolid which separated was collected, washedwith water, and dried over sulfuric acid to give 22.1 g. of 5-(2-heptyl)resorcinol which was not purified further.

(B) 2-benzyl-8-(2-heptyl) -10-hydroxy-5-oxo-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d1pyridine Following a proceduresimilar to that described in Example 1 hereinabove,N-benzyl-4-carbethoxy-3-piperidone hydrochloride is reacted with5-(2-heptyl)resorcinol in the presence of concentrated sulfuric acid andphosphorus oxychloride to give 2-benzyl-8-(2-heptyl)-10-hydroxy 5 oxo1,2,3,4-tetrahydro-5H-[1]benzopyrano [3,4-d]pyridine.

The latter, on reaction with methyl magnesium iodide according to theprocedure of Example 1 hereinabove, gives Z-benzyl 5,5 dimethyl8-(2-heptyl)-10-hydr0xy- 1,2,3,4-tetrahydro-5H-[ 1 benzopyrano[ 3,4-d]pyridine.

EXAMPLE 5 (A) 5 l-cyclohexylethyl resorcinol To a solution of cyclohexylmagnesium chloride [prepared from 177.1 g. (1.5 moles) ofchlorocyclohexane and 24.3 g. (1.0 g. atom) of magnesium] in 300 ml. ofether was added 45.2 g. (0.25 mole) of 3,5-dimethoxybenzamide inportions over a period of one hour The mixture was stirred and refluxedfor fifty hours, allowed to stand at room temperature for sixty-fourhours, and then poured into one liter of crushed ice and watercontaining ml. of concentrated sulfuric acid. The organic layer wasseparated, the aqueous phase extracted with ether, and the combinedether extracts washed with saturated sodium chloride, dried overanhydrous magnesium sulfate, charcoaled, filtered, and taken to drynessyielding an oil which was distilled in vacuo to give 39.3 g. ofcyclohexyl 3,5-dimethoxyphenyl ketone, B.P. 141-162" C./.01 mm., 111.5403.

The latter (39 g., 0.157 mole), dissolves in 200 ml. of ether, wasreacted with 0.2 mole of methyl magnesium iodide following a proceduresimilar to that used in Example 4(A) hereinabove to give 40.6 g. of1-cyclohexyl-1-(3,5-dimethoxyphenyl)-ethanol.

The latter was reacted with 1.0 ml. of 20% sulfuric acid at 130-140 C.for thirty minutes following a procedure similar to that used in Example4(A) hereinabove to give 27.7 g. of [1-(3,5-dimethoxyphenyl)ethylidenyl]cyclohexane, B.P. 114120 C./0.1 mm., 11 1.5408.

The latter (27 g., 0.11 mole) was reduced with hydrogen over Raneynickel following a procedure similar to that used in Example 4(A)hereinabove to give 20.8 g. of 5-(1-cyclohexylethyl) 1,3dimethoxybenzene, B.P. 115118 C./0.12 mm., n 1.5262. The latter (0.084mole) was demethylated with 84 ml. of hydriodic acid in 84 ml. of aceticanhydride following a procedure similar to that used in Example 4(A)hereinabove to give 14.7 g. of 5-(l-cyclohexylethyl)resorcinol, M.P.6569 C.

(B) 2-benzyl-8- l-cyclohexylethyl) -10-hydroxy-5-oxo-1,2,3,4-tetrahydro-5H-[1]benzopyranro[3-4-d]pyridine Following a proceduresimilar to that described in Example 1 hereinabove,N-benzyl-4-carbethoxy-3-piperidone hydrochloride is reacted with5-(1-cyclohexylethyl)resorcinol in the presence of concentrated sulfuricacid and phosphorus oxychloride to give2-benzyl-8-(l-cyclohexylethyl)-10-hydroxy 5 oxo-1,2,3,4tetrahydro-5H-[1]benzopyrano [3,4-d] pyridine and 2-benzyl-10-(l-cyclohexylethyl)-8-hydroxy 5-ox0-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d] pyridine.

The latter, on reaction with methyl magnesium iodide according to theprocedure of Example 1 hereinabove, gives respectively,2benzyl-8-(l-cyclohexylethyl)-5,5-dimethyl 10hydroxy-l,2,3,4-tetrahydro-5H[1]benzopyrano[3,4-d]pyridine and2-benZyl-10-(l-cyclohexylethyl-5,5dimethyl-8-hydroxy-1,2,3,4-tetrahydro-5H [1]benzopyrano 3,4-d]pyridine.

EXAMPLE 6 (A) 5-(3-cyclopropyl-2-propyl)resorcinol By reactingcyclopropylmethyl magnesium bromide with 3,5-dimethoxybenzamide;reacting the resulting cyclopropylmethyl 3,5-dimethoxyphenyl ketone withmethyl magnesium iodide; dehydrating the resultingl-eyclopropyl-2-(3,5-dimethoxyphenyl)-2-propanol with 20% sulfuric acid;reducing with hydrogen over Raney nickel the resulting1-cyclopropyl-2-(3,5-dimethoxyphenyl) 1-propene; and demethylating theresulting 1-cyclopropyl-2-(3, 5-dimethoxphenyl)propane with hydriodicacid in acetic anhydride using the manipulative procedures given abovein Examples 4(A) and 5(A), there is obtained 5-(3-cyclopropyl-Z-propyl)resorcinol.

(B) 2-benzyl-8 (3-cyclopropyl-2-propyl) 10-hydroxy-5-oXo-1,2,3,4-tetrahydro 5H [l]benzopyrano[3,4-d] pyridine Following aprocedure similar to that described in Example 1 hereinabove,N-benzyl-4-carbethoxy-3-piperidone is reacted with5-(3-cyc1opropyl-2-propyl)resorcinol to give2-benzyl-8-(3-cyclopropyl-2-propyl) 10-hydroxy-5- gxo-1,2,3,4-tetrahydro5H [1]benzopyrano[3,4-d]pyriine.

The latter, on reaction with methyl magnesium iodide according to theprocedure of Example 1 hereinabove, gives 2-benzyl-8(3-cyclopropyl-2-propyl)-5,5-dimethyl- 10-hydroxy 1,2,3,4tetrahydro-H-[l]benzopyrano[3, 4-dJPYIidine.

EXAMPLE 7 (A) 5-(2-tetradecyl)resorcinol Following a procedure similarto that described in EX- ample 5 (A) hereinabove, 0.2 mole of a Grignardreagent prepared from 60 g. (0.24 mole) of l-bromododecane and 4.8 g.(0.20 atom) of magnesium was reacted with 9.05 g. (0.05 mole) of3,5-dimethoxybenzamide in diethyl ether, and the resulting l-dodecyl3,5-dimethoxyphenyl ketone (43 g., 0.13 mole) was reacted with methylmagnesium iodide using a procedure similar to that used in Example 4(A)hereinabove. Dehydration of the resulting2-(3,5-dimethoxyphenyl)-2-tetradecan0l (13.5 g., 0.039 mole) with 1 ml.of 20% sulfuric acid to the corresponding2-(3,5-dimethoxyphenyl)-2-tetradecene, catalytic reduction of the latter(26 g., 0.078 mole) with hydrogen over 6 g. of Raney nickel and cleavageof the resulting 2- (3,5-dimethoxyphenyl)tetradecane (20 g., 0.06 mole)with 60 ml. of 57% hydriodic acid in 60 ml. of acetic anhydride, allaccording to the procedures described in Example 4(A) hereinabove,afforded 15.7 g. of 5-(2-tetradecyl)resorcino1, M.P. 6l63 C.

(B) 2-benzy1-10-hydroxy-5-oxo-8-(2-tetradecyl)-1,2,3,4-

tetrahydro-5H-[ l benzopyrano 3,4-d] pyridine Following a proceduresimilar to that described in Example 1 hereinabove,N-benzyl-4-carbethoxy-3-piperidone is reacted with5-(2-tetradecyl)resorcinol in the presence of concentrated sulfuric acidand phosphorus oxychloride to give2-benzyl-10-hydroxy-5-oxo-8-(Z-tetradecyl)-1,2,3, 4tetrahydro-5H-[l]benzopyranol 3,4-d] pyridine.

The latter, on reaction with methyl magnesium iodide following theprocedure of Example 1 hereinabove, gives2-benzyl-5,5-dimethyl-l0-hydroxy-8 (2-tetradecyl)1,2,3, 4-tetrahydro-5H-1]benzopyrano [3,4-d] pyridine,

EXAMPLE 8 (A) 5-(2-eicosyl)resorcinol Following a procedure similar tothat used in Example 5(A) hereinabove, a Grignard reagent, prepared from333.4 g. (1.0 mole) of l-brornooctadecane and 24.3 g.

(1.0 g. atom) of magnesium in 500 ml. of anhydrous ether was treatedwith 45.2 g. (0.25 mole) of 3,5-dimethoxybenzamide to give 58.9 g. ofl-octadecyl 3,5-

dimethoxyphenyl ketone, M.P. 6771 C.

The latter (56.5 g., 0.135 mole), slurried in 600 ml. of anhydrous etherand 100 ml. of tetrahydrofuran, was reacted with 0.2 mole of freshlyprepared methyl magnesium iodide in 100 ml. of anhydrous ether followinga procedure similar to that used in Example 4(A) hereinabove to give48.1 g. of 2-(3,5-dimethoxyphenyl)-2-eicosanol, M.P. 5154 C.

The latter (27.1 g., 0.085 mole) was reacted with 1.0 ml. of 20%sulfuric acid at 130140 C. for thirty minutes following a proceduresimilar to that used in Example 4(A) hereinabove to give 19.2 g. of2-(3,5-dimethoxyphenyl)-2-eicosane, M.P. 35-37 C.

The latter (19 g., 0.046 mole) was reduced with hydrogen over 3 g. ofRaney nickel following a procedure similar to that used in Example 4(A)hereinabove to give 14.8 g. of 2-(3,5-dimethoxyphenyl)eicosane which wasdemethylated with 35 ml. of 57% hydriodic acid in 35 ml. of aceticanhydride following a procedure similar to that used in Example 4(A)hereinabove to give 11.5 g. of 5- (2-eicosyl)resorcinol, M.P. 75 .576.5C.

(B) 2-benZyl-8- (2-eicosyl 1 O-hydroxy-S-oxo- 1,2,3 ,4- tetrahydro-SH- 1]benzopyrano [3 ,4-d] pyridine Following a procedure similar to thatused in Example 1 hereinabove, N-benzyl4-carbethoxy-3-piperidone v 10 isreacted with 5-(2-eicosyl)resorcinol to give 2-benzyl-8- (Z-eicosyl)10-hydroxy-5-oxo-l,2,3,4-tetrahydro-5H-[l] benzopyrano[3,4-d]pyridine.

The latter, on reaction with methyl magnesium iodide according to theprocedure of Example 1 hereinabove, gives 2 benzyl-5,5dimethyl-8-(2-eicosyl)-10-hydroxy- 1,2,3,4-tetrahydro-5H-[1]benzopyrano[3 ,4-d] pyridine.

EXAMPLE 9 10 hydroxy 8 (3-methyl-2-octyl)5-0xo-l,2,3,4- tetrahydro-5H-[l benzopyrano [3 ,4-d] pyridine A solution of 2 g. (0.0046 mole) of2-benzyl-10-hydroxy 8 (3 methyl 2 octyl) 5 oxo 1,2,3,4-tetrahydro-5H-[1]-benzopyrano[3,4-d]pyridine in ml. of absolute ethanoland 10 ml. of glacial acetic acid was shaken with hydrogen at a pressureof 48.5 pounds p.s.i. in the presence of 0.5 g. of 10%palladium-on-charcoal. Reduction was complete after about 16 hours, andthe mixture was then filtered, the filtrate evaporated to dryness, andthe residue dissolved in chloroform and neutralized with aqueouspotassium bicarbonate. The chloroform layer was filtered and evaporatedto dryness, and the solid residue was recrystallized from acetonitrilegiving 0.5 g. of 10 hydroxy 8 (3-methyl-2-octyl)-5-oxo- 1,2,3,4tetrahydro 5H-[1]benzopyrano[3,4-d1pyridine, M.P. 172-175 C.

The latter, on reaction with methyl magnesium iodide according to theprocedure of Example 1 hereinabove, gives 5,5 dimethyl 10 hydroxy 8 (3methyl 2- octyl) l,2,3,4 tetrahydro 5H [1]benzopyrano[3,4dl' pyridine.

EXAMPLE 10 10-hydroxy-8-methyl-5-oxo-1,2,3 -tetrahydro-5H-[1]benzopyrano [3,4-d] pyridine Following a procedure similar to thatdescribed in Example 9 hereinabove, 2-benzyl-10-hydroxy-8-methyl-5- oxo1,2,3,4 tetrahydro 5H [l]benzopyrano[3,4-d] pyridine is catalyticallydebenzylated with hydrogen in the presence of palladium-on-charcoal togive 10-hydroxy-8- methyl- 5 oxo l,2,3,4 tetrahydro-5H-[1]benzopyrano[3,4-d1pyridine.

The latter, on recation with methyl magnesium iodide according to theprocedure of Example 1 hereinabove, gives 5,5-dimethyl-10-hydroxy 8methyl 1,2,3,4-tetrahydro-5H- 1 -benzopyrano [3,4-d] pyridine.

EXAMPLE l l 8-( l-cyclohexylethyl)-l0-hydroxy-5-oxo-1,2,3,4-tetrahydro-SH- 1 benzopyrano [3 ,4-d] pyridineFollowing a procedure similar to that described in Example 9hereinabove, 2-benzyl-8-(l-cyclohexylethyD- 10 hydroxy 5 oxo1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine is catalyticallydebenzylated with hydrogen in the presence of palladium-on-charcoal togive 8 (1 cyclohexylethyl) 10-hydroxy-5-oxo-1,2,3,4- tetrahydro-SH-1]benzopyran0[3,4-d] pyridine.

The latter, on reaction with methyl magnesium iodide according to theprocedure of Example 1 hereinabove, gives 8 (1cyclohexylethyl)-5,5-dimethyl-10-hydroxyl,2,3,4-tetr ahydro-5H-[ 1benzopyrano[3,4-d pyridine.

EXAMPLE 12 8-(3-cycl0propyl-2-propyl)-10-hydroxy-5-oxo-1,2,3,4-

tetrahydro-SH- l]benzopyrano [3,4-d1pyridine Following a proceduresimilar to that described in Example 8 hereinabove, 2 benzyl 8(3-cyclopropyl-2- propyl) 1O hydroxy 5 oxo 1,2,3,4 tetrahydro 5H-[1]benzopyrano[3,4-d]pyridine is catalytically debenzylated withhydrogen in the presence of palladium-on-charcoal to give 8 (3cyclopropyl-Z-propyl)-10-hydroxy-5- oxo 1,2,3,4 tetrahydro 5H[1]benzopyrano[3,4-d]- pyridine.

1 1 The latter, on reaction with methyl magnesium iodide according tothe procedure of Example 1 hereinabove, gives 8 (3 cyclopropyl 2 propyl)10 hydroxyl,2,3,4 tetrahydro 5H-[l]benzopyrano[3,4-d] pyridine.

EXAMPLE l3 S-(Z-eicosyl -l'hydroxy-5-oxo-1,2,3,4-tetrahydro- 5H[ 1benzopyrano[3,4-d] pyridine Following a procedure similar to thatdescribed in Example 9 hereinabove, 2 benyl 8 (2 eicosyl) l0- hydroxy 5oxo l,2,3,4-tetrahydro-5H-[l]benzopyrano [3,4-d1pyridine iscatalytically debenzylated with hydrogen in the presence ofpalladium-on-charcoal to give 8-(2- eicosyl) 10 hydroxy 5 oxol,2,3,4-tetrahydro-5H- l1benzopyrano[3,4-d]pyridine.

The latter, on reaction with methyl magnesium iodide according to theprocedure of Example 1 hereinabove, gives 5,5 dimethyl 8(Z-eicosyl)-l0-hydroxy-1,2,3,4- tetrahydro-5H-[l1benzopyrano[3,4-d1pyridine.

EXAMPLE 14 10 hydroxy 8 (3-methyl-2-octyl)-2-[l-(2-propynyl)]- 5 oxo1,2,3,4 tetrahydro 5H [11benzopyrano [3 ,4-d] pyridine hydrochloride Amixture of 1.42 g. (0.004 mole) of 10 hydroxy-8- (3 methyl 2 octyl) 5oxo 1,2,3,4-tetrahydro 5H- [1]benzopyrano[3,4-d] pyridine hydrochloride,0.48 g. (0.004 mole) of 3-bromo-l-propyne, and 0.6 g. of anhydroussodium carbonate in ml. of absolute ethanol was refluxed for 16 hours,cooled, and filtered. The filtrate was evaporated to dryness, theresidue was extracted with boiling acetonitrile, and the extract cooledovernight in a refrigerator to remove a small quantity of a dark brownprecipitate. After removal of the latter, the supernatant liquid wasevaporated to drynes, the resulting solid was dissolved in ahexane/ether mixture, and the mixture cooled in an ice bath to cause theprecipitation of a dark gum which was separated by decantation. Thesolution was evaporated to dryness once more, taken into ether, and thesolution saturated with anhydrous hydrogen chloride. There was thusobtained 0.8 g. of 10-hydroxy-8-(3- methyl 2 octyl) 2[l-(2-propynyl)]-5-oxo-l,2,3,4- tetrahydro 5H[l]benzopyrano[3,4-d1pyridine hydrochloride as a light tan crystallinesolid, M.P. 127l31 C. (uncorr.).

The latter, on reaction with methyl magnesium iodide according to theprocedure of Example 1 hereinabove, gives 5,5 dimethyl l0 hydroxy 8 (3methyl 2- octyl) 2 [1 (2-propynl)]-1,2,3,4-tetrahydro-5H-[l]benzopyrano[3,4-d] pyridine.

EXAMPLE 15 10-hydroxy-8-methyl-5-oxo-2-[ l-(Z-propynyl) ]-1,2,3,4-tetrahydro-SH- [l benzopyrano [3,4-d] pyridine Proceeding in a mannersimilar to that described in Example 14 hereinabove, 1O hydroxy 8methyl-S-oxol,2,3,4 tetrahydro-5H-[l]benzopyrano[3,4-d] pyridine isreacted with 3-bromo-1-propyne in absolute ethanol in the presence ofanhydrous sodium carbonate to give 10-hydroxy 8methyl-5-oxo-2-[1-(2-propynyl) ]-l,2,3,4-tetrahydro-5H-[1]ber1zopyrano[3,4-d]pyridine.

The latter, on reaction with methyl magnesium iodide according to theprocedure of Example 1 hereinabove, gives 5,5 dimethyl 10 hydroxy 8methyl 2-[1-(2- propynyl)] 1,2,3,4 tetrahydro 5H [llbenzopyrano [3,4-d]pyridine.

EXAMPLE 16 8- l-cyclohexylethyl) -10-hydroxy-5-oxo2- l- (2 propynyl)]1,2,3,4 tetrahydro 5H [l]benzopyrano[3,4-d] pyridine Following aprocedure similar to that described in Example 14 hereinabove,8-(l-cyclohexylethyl)-l0-hydroxy- 12 5-oxo 1,2,3,4 tetrahydro 5H[1]benzopyrano[3,4-d] pyridine is reacted with 3-bromo-1-propyne inabsolute ethanol in the presence of anhydrous sodium carbonate to give8-(1-cyclohexylethyl)-10-hydroxy-5-oxo-2-[1-(2- propynyl)] 1,2,3,4tetrahydro 5H [l]benzopyrano- [3,4-d]pyridine.

The latter, on reaction with methyl magnesium iodide according to theprocedure of Example 1 hereinabove, gives 8-( 1-cycl0hexylethyl)-5,S-dimethyl-10-hydroxy-2- l- (2 propynyl)] 1,2,3,4tetrahydro-5H-[l]benzopyrano- [3,4-d1pyridine.

EXAMPLE 17 8-(3-cyclopropyl-2-propyl) 10 hydroxy-2-[1-(2-propynyl)] 5oxo 1,2,3,4 tetrahydro-5H-[1]benzopyrano- [3,4-d1pyridine Following aprocedure similar to that described in Example 14 hereinabove,8-(3-cyclopropyl-2-propyl)-10- hydroxy-S-oxo 1,2,3,4tetrahydro-5H-[l]benzopyrano- [3,4-d] pyridine is reacted with3-bromo-l-propyne in absolute ethanol in the presence of anhydroussodium carbonate to give 8-(3-cyclopropyl-2-propyl)-l0-hydroxy-2-[l-(2-propynyl)] 5 oxo 1,2,3,4 tetrahydro-SH-[l] benzopyrano [3 ,4-d]pyridine.

The latter, on reaction with methyl magnesium iodide according to theprocedure of Example 1 hereinabove, gives 8-(3-cyclopropyl 2 propyl) 5,5dimethyl-lO-hydroxy-2-[1-(2-propynyl)] 1,2,3,4 tetrahydro 5H [1]benzopyrano [3 ,4-d] pyridine.

EXAMPLE l8 8-(2-eicosyl) 10 hydroxy 5 oxo-2-[1-(2-propynyl)]-1,2,3,4-tetrahydro-5H-[ l benzopyrano[3,4-d] pyridine Following aprocedure similar to that described in Example 14 hereinabove,8-(2-eicosyl)-10-hydroxy-5-oxo- 1,2,3,4 tetrahydro-SH- 1 ]benzopyrano[3,4-d] pyridine is reacted with 3-bromo-l-propyne in absolute ethanolin the presence of anhydrous sodium carbonate to give 8-(2-eicosyl) 1Ohydroxy 5 oxo-2[1-(2-propynyl)]- 1,2,3,4-tetrahydro-5H-[l]benzopyrano[3,4-d] pyridine.

The latter, on reaction with methyl magnesium iodide according to theprocedure of Example 1 hereinabove, gives 5 ,5 -dimethyl-8-(2-eicosyl))-10-hydroxy-2-[1-(2-propynyl)] 1,2,3,4tetrahydro-5H-[1]benZopyrano[3,4-d] pyridine.

EXAMPLE 19 Z-cinnamyl-10-hydroxy-8-(3-methyl-2-octyl)-S-oxo-1,2,3,4-tetrahydro-5H-[ l benzopyrano 3,4-d] pyridine Following a proceduresimilar to that described in Example 14 hereinabove,10-hydroxy-8-(3-methyl-2-octyl)- 5 oxo 1,2,3,4tetrahydro-5H-[l]benzopyrano[3,4-d] pyridine is reacted with cinnamylchloride in absolute ethanol in the presence of anhydrous sodiumcarbonate to give 2-cinnamyl-l0-hydroxy-8-(3-methyl-2-octyl)-5- oxo1,2,3,4 tetrahydro 5H [1]benzopyrano[3,4-d] pyridine.

The latter, on reaction with methyl magnesium iodide according to theprocedure described above in Example 1, gives2-cinnamyl-5,5-dimethyl-10-hydroxy-8-(3-methyl-2- octyl) 1,2,3,4tetrahydro 5H [1]benzopyrano[3,4-d] pyridine.

EXAMPLE 20 10-hydroxy-8-(3-methyl 2 octyl) 5 oxo-2-(2-phenylethyl)1,2,3,4 tetrahydro-SH-[l]benZopyrano[3,4-d] pyridine Following aprocedure similar to that described in Example 14 above,10-hydroxy-8-(3-methyl-2-octyl)-5-ox0- 1,2,3,4 tetrahydro 5H[1]benzopyrano[3,4-d]pyridine is reacted with 2-phenylethyl bromide inabsolute ethanol in the presence of anhydrous sodium carbonate to give10-hydroxy-8-(3 methyl 2 octyl)-5-oxo-2-(2-phenylethyl) l,2,3,4tetrahydro 5H [1]benzopyrano[3,4-d] pyridine.

The latter, on reaction with methyl magnesium iodide according to theprocedure described above in Example 1, gives 5 ,5 -dimethyl- 1-hydroxy-8- 3-methyl-2-octyl) -2- (2- phenylethyl) 1,2,3,4 tetrahydro H[1]benzopyrano- [3,4-d]pyridine.

EXAMPLE 21 -hydroxy-8-(3-methyl-2-octyl) 2 [2-(4-methylphenyl)ethyl]-5-oxo 1,2,3,4 tetrahydro-5H-[1]benzopyrano- [3 ,4-d] pyridineFollowing a procedure similar to that described in EX- ample 14hereinabove, 10-hydroxy-8-(3-methyl-2-octyl)- 5-oxo 1,2,3,4 tetrahydro5H [1]benzopyrano[3,4-d] pyridine is reacted with2-(4-methylphenyl)ethyl bromide in absolute ethanol in the presence ofanhydrous sodium carbonate to give 10-hydroxy-8-(3-methyl-2-octyl)-2-[2-(4-methylphenyl)ethyl] 5 oxo 1,2,3,4 tetrahydro-SH- [1]benzopyrano3,4-d] pyridine.

The latter, on reaction with methyl magnesium iodide according to theprocedure described above in Example 1, gives 5 ,5 -dimethyl- 10-hydroxy-8- 3-methyl-2-octyl -2- [2- (4 methylphenyl)ethyl] 1,2,3,4tetrahydro 5H [1] benzopyrano [3,4-d] pyridine.

EXAMPLE 22 10-hydroxy-8-(3-methyl-2-octyl) 2[3-(3,4-dimethoxyphenyl)propyl] 5 oxo 1,2,3,4 tetrahydro-SH-[l]benzopyrano [3 ,4-d] pyridine Following a procedure similar to thatdescribed in Example 14 hereinabove, 10-hydroxy-8-(3-methyl-2-octyl)-5-oxo 1,2,3,4 tetrahydro 5H [1]benzopyrano[3,4-d] pyridine is reactedwith 3-(3,4-dimethoxyphenyl)propyl bromide in absolute ethanol in thepresence of anhydrous sodium carbonate to give10-hydroxy-8-(3-methyl-2-octyl)- 2-[3-(3,4-dimethoxyphenyl)propyll] 5oxo-1,2,3,4-tetrahydro-5H-[ 1 benzopyrano [3,4-d] pyridine The latter,on reaction with methyl magnesium iodide according to the proceduredescribed in Example 1 here inabove, gives5,5-dimethyl-10-hydroxy-8-(3-methyl-2- octyl) 2- 3- 3 ,4-dimethoxyphenyl)propyl] -1,2,3,4-tetrahydro-SH- 1 benzopyrano 3,4-d] pyridine.

EXAMPLE 23 10 hydroxy 8- 3-methyl-2-octyl -5-oxo-2-[ 1-2,4,6-tribromophenyl) ethyl]-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d] pyridine Following a procedure similar to that described inExample 14 hereinabove, l0 -hydroxy-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-5H- 1 benzopyrano [3,4 d] pyridine is reactedwith 1- (2,4,6tribromophenyl)ethyl bromide in absolute ethanol in thepresence of anhydrous sodium carbonate to give10-hydroxy-8-(3-methyl-2-octyl) 5-oxo-2-[1-(2,4,6-tribromophenyl)ethyl]-1,2,3,4-tetrahydro-SH-[l]benzopyrano[3,4-d]pyridine.

The later, on reaction with methyl magnesium iodide according to theprocedure described in Example 1 hereinabove gives 5,5-dimethyl 10hydroxy-8-(methyl-2-octyl) 2-[1-(2,4,6-tribromophenyl)ethyl]-l,2,3,4-tetrahydro-S-H- 1 benzopyrano3,4-d] pyridine.

EXAMPLE 24 10-hydroxy-8-(3-methyl 2 octyl)-2-[4-(4-nitrophenyl) butyl] 5oxo-l,2,3,4-tetrahydro-5H[1]benzopyrano [3,4,-d]pyridine Following aprocedure similar to that described in Example 14 hereinabove,lO-hydroxy-8-(3-methyl-2-octyl)5-oxo-l,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d] pyridine is reactedwith 4-(4-nitrophenyl)butyl bromide in absolute ethanol in the presenceof anhydrous sodium carbonate to give10-hydroxy-8-(3-methyl-2-octyl)-2-[4- (4 nitrophenyDbutyl]5-oxo-1,2,3,4-tetrahydro-5H-[1] benzopyrano 3 ,4-d] pyridine.

The latter, on reaction with methyl magnesium iodide according to theprocedure of Example 1 hereinabove,

14 gives 5,5-dimethyl-10-hydroxy-8-(3-methy1 2 octyl)-2-[4-(4-nitrophenyl)-butyl] 1,2,3,4 tetrahydro 5H [1] benzopyrano [3,4-d]pyridine.

EXAMPLE 25 l0-hydroXy-8-(methyl-2-octyl)-2-[2-(4 methylmercaptophenylethyl] 5-oxo-l,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridineFollowing a procedure similar to that described in Example 14hereinabove, 10-hydroxy-8-(3-methyl-2-octyl)-5'-oxo-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4 d]pyridine. is reactedwith 2-(4-methylmercaptophenyl)ethyl bromide in absolute ethanol in thepresence of anhydrous sodium carbonate to give10-hydroxy-8-(3-methyl-2-octyl)2-[2-(4-methylmercaptophenyl)ethyl]-5-oxo-1,2,3, 4-tetrahydro-5H-1]benzopyrano [3,4-d] pyridine.

The latter, on reaction with methyl magnesium iodide according to theprocedure described in Example 1 hereinabove, gives5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl) 2- [2-(4-methylmercaptophenyl)ethyl] -1,2,3,4-tetrahydro-5H-[ 1 benzopyrano[3,4-d] pyridine.

EXAMPLE 26 10-hydroxy-8-( 3-methyl-2-octyl) -2-{1 [3(3,4-methylenedioxyphenyl)-2-butenyl] }-5-oxo-1,2,3,4 tetrahydro- 5H-[1]benzopyrano 3,4-d] pyridine Following a procedure similar to thatdescribed in Example 14 hereinabove, lO-hydroxy-S-(3-methyl-2-octyl) 5oxo-l,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4 d]pyridine is reacted with3-[1-(3,4-methylenedioxyphenyl)-l-butenyl] bromide in absolute ethanolin the presence of anhydrous sodium carbonate to give IO-hydroxy- 8 (3methyl-Z-octyl)-2-{1-[3-(3,4-methylenedioxyphenyl) 2 butenyl]} 5oxo-1,2,3,4-tetrahydro-5H-[1]benzopyrano-[3,4-d]pyridine.

The latter, on reaction with methyl magnesium iodide according to theprocedure described in Example 1 hereinabove, gives5,5-dimethyl-10-hydroxy-S-(3-methyl-2-octyl) 2{1-[3-(3,4-methylenedioxyphenyl)-2-butenyl]}- 1,2,3,4-tetrahydro-5H-[l]benzopyrano[3,4-d]pyridine.

EXAMPLE 27 10 hydroxy8-(3-methyl-2-octyl)-5-oxo-2-{1-[4-(3-trifluoromethylphenyl) 3butenyl]}-1,2,3,4-tetrahydro- 5H-[ 1]benzopyrano [3 ,4-d] pyridineEXAMPLE 28 2 allyl 10-hydroxy-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-SH- 1 benzopyrano [3 ,4-d] pyridine Following a proceduresimilar to that described in Ex ample 14 hereinabove,10-hydroxy-8-(3-methyl-2-octyl)- 5 oxo1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d] pyridine is reacted withallyl bromide in absolute ethanol in the presence of anhydrous sodiumcarbonate to give 2 allyl 10-hydroxy-8(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-SH- 1 benzopyrano 3,4-d] pyridine.

The latter, on reaction with methyl magnesium iodide according to theprocedure of Example 1 hereinabove, gives 2allyl-5,5-dirnethyl-10-hydroxy-8-(3-methyl-2-oc- 15 tyl) l,2,3,4tetrahydro-5H-[l]benzopyrano[3,4-d]pyridine.

EXAMPLE 29 10 hydroxy 2 [1-(3-methyl-2-butenyl)]-8-(3-methyl- 2octyl)-5-oxo-1,2,3,4-tetrahydro-5H-[ 11benzopyrano [3,4-d]pyridineFollowing a procedure similar to that described in Example 14hereinabove, 10-hydroxy-8-(3-methyl-2-octyl) 5x0-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4- d]pyridine is reacted with1-bromo-3-methyl-2-butene in absolute ethanol in the presence of sodiumcarbonate to give 10-hydroxy-2-[1-(3-methyl-2-butenyl) ]-8- 3-methyl- 2octyl) -oxo-1,2,3,4-tetrahydro-5H-[1]benzopyrano [SA-d]pyridine.

The latter, on reaction with methyl magnesium iodide according to theprocedure of Example 1 hereinabove, gives 5,5 dimethyl hydroxy 2[1-(3-methyl-2- butenyl)] 8 (3 methyl-2-octyl)-1,2,3,4-tetrahydro- 5H[1]benzopyrano[3,4-d1pyridine.

EXAMPLE 2 [1 (trans 3 chloro 2 propenyl)] 10 hydroxy 8 (3 methyl 2octyl) 5 oxo 1,2,3,'4- tetrahydro-5H[ 1 benzopyrano 3,4-d] pyridineFollowing a procedure similar to that described in Example 14 above,10-hydroxy-8-(3-methyl-2-octyl)-5- oxo 1,2,3,4 tetrahydro 5H[1]benzopyrano[3,4-d] pyridine is reacted withtrans-1,3-dichloro-2-propene in absolute ethanol in the presence ofanhydrous sodium carbonate to give 2-[l-(trans-3-chloro-2-propenyl)1-10-hydroxy 8 (3-methyl-2-octyl)-5-oxo-1,2,3,4tetrahydro- 5H-[ l]benzopyrano3,4-d1pyridine.

The latter, on reaction with methyl magnesium iodide 7 EXAMPLE 31 2 [l(cis 3 chloro 2 propenyl)] 10 hydroxy- 8 (3 methyl 2 octyl) 5 oxo1,2,3,4 tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine Following aprocedure similar to that described in Example 14 hereinabove,IO-hydroxy-S-(3-methyl-2-octyl)- 5 oxo 1,2,3,4 tetrahydro5H-[1]benzopyrano[3,4- d]pyridine is reacted withcis-l,3-dichloro-2-propene in absolute ethanol in the presence ofanhydrous sodium carbonate to give2-[1-(cis-3-chloro-2-propenyl)]-10-hydroxy 8 (3 methyl 2octyl)-5-oxo-1,2,3,4-tetrahydro-SH- 1 ]benzopyrano [3 ,4-d] pyridine.

The latter, on reaction with methyl magnesium iodide according to theprocedure of Example 1 hereinabove, gives 2 [1 (cis 3 chloro 2propenyl)]-5,5-dimethyl 10 hydroxy 8 (3methyl-2-octyl)-1,2,3,4-tetrahydro-SH- 1 benzopyrano [3,4-d] pyridine.

EXAMPLE 32 2 cyclobutylmethyl 10 hydroxy 8 (3 methyl 2- octyl) 5 oxo1,2,3,4 tetrahydro 5H [1]benzopyrano[3,4-d] pyridine Following aprocedure similar to that described in Example 14 hereinabove,10-hydr0xy-8-(3-methyl-2- octyl) 5 oxo1,2,3,4-tetrahydro-5H-[1]benzopyrano [3,4-d]pyridine is reacted withcyclobutylmethyl chloride in absolute ethanol in the presence of sodiumcarbonate to give 2 cyclobutylmethyl 10-hydroxy-8-(3-methyl-2- octyl) 5oxo l,2,3,4 tetrahydro 5H [1]benzopyrano [3,4-d] pyridine.

The latter, on reaction with methyl magnesium iodide according to theprocedure described in Example 1 above, gives 2 cyclobutylmethyl 5,5dimethyl 10 hydroxy- 8 (3methyl-Z-octyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine.

1 6 EXAMPLE 33 2 cyclopropylmethyl 1O hydroxy 8 (3 methyl- 2 octyl) 5oxo 1,2,3,4 tetrahydro 5H [1] benzopyrano [3 ,4-d] pyridine Following aprocedure similar to that described in Example 14 hereinabove,10-hydroxy-8-(3-methyl-2- octyl) 5 oxo 1,2,3,4 tetrahydro 5H[1]benzopyrano[3,4-d]pyridine is reacted with cyclopropylmethyl chloridein absolute ethanol in the presence of sodium carbonate to give2-cyclopropylmethyl-10-hydroxy-8-(3- methyl 2 octyl) 5oxo-1,2,3,4tetrahydro-5H-[l] benzopyrano [3 ,4-d] pyridine.

The latter, on reaction with methyl magnesium iodide according to theprocedure described in Example 1 hereinabove, gives 2 cyclopropylmethyl5,5 dimethyl-10- hydroxy 8 (3 methyl 2 octyl)-1,2,3,4-tetrahydro- SH- 1benzopyrano [3,4-d] pyridine.

EXAMPLE 34 10 hydroxy 8 (3 methyl 2 octyl) 5 oxo 2- [l (3 phenyl 2propynyl)] 1,2,3,4 tetrahydro- 5H-[ 1 benzopyrano [3,4-d] pyridineFollowing a procedure similar to that described in Example 14hereinabove, IO-hydroxy 8 (3-methyl-2- octyl) 5 oxo 1,2,3,4tetrahydro-SH-[l]benzopyrano [3,4-d] pyridine is reacted with3-pheny1-2-propynyl bromide in absolute ethanol in the presence ofanhydrous sodium carbonate to give 10-hydroxy-8-(3-methyl-2- octyl) 5oxo 2 [l-(3-phenyl-2-propynyl)]-1,2,3,4- tetrahydro-5H-[ l benzopyrano[3,4-d] pyridine.

The latter, on reaction with methyl magnesium iodide according to theprocedure described in Example 1 hereinabove, gives5,5-dimethyl-l0-hydroxy-8-(3-methyl-2- octyl) 2 [1 (3phenyl-Z-propynyl)]-1,2,3,4-tetrahydro-5H-[ 1 benzopyrano [3 ,4-d]pyridine.

EXAMPLE 35 10 hydroxy 8 (3 methyl 2 octyl) 5 oxo 2- {1 [3 (2,4,6trimethylphenyl)-2-propynyl}-1,2,3, 4 tetrahydro 5H[1]benzopyrano[3,4-d]pyridine Following a procedure similar to thatdescribed in Example 14 hereinabove, 1O hydroxy 8-(3-methyl-2- octyl) 5oxo 1,2,3,4 tetrahydro 5H [1]benzopyrano[3,4-d]pyridine is reacted with3-bromo-1-mesityll-propyne in absolute ethanol in the presence ofanhydrous sodium carbonate to give l0-hydroxy-8-(3-methyl- 2-octyl) 5oxo 2 {1-[3-(2,4,6-trimethylpheny1)-2- propynyl]} 1,2,3,4 tetrahydro 5H[1]benzopyrano [3,4-d1pyridine.

The latter, on reaction with methyl magnesium iodide according to theprocedure described in Example 1 hereinabove, gives 5,5 dimethyl 10hydroxy 8 (3- methyl 2 octyl) 2 {1 [3 (2,4,6-trimethylphenyl)- 2propynyl]} 1,2,3,4 tetrahydro 5H [1]benzopyrano[3,4-d]pyridine.

EXAMPLE 36 10 hydroxy 8 (3 methyl 2 octyl) 5 0x0 2- {1 [3 (4methylphenyl) 2 propynyl]} 1,2,3,4- tetrahydro-SH- 1 benzopyrano 3,4-d]pyridine Following a procedure similar to that described in Example 14hereinabove, 10 hydroxy 8 (3-methyl-2- octyl) 5 oxo 1,2,3,4tetrahydro-5H-[1]benzopyrano [3,4-d]pyridine is reacted with3-chloro-1-(4-methylphenyl)-1-propyne in absolute ethanol in thepresence of anhydrous sodium carbonate to give 10-hydroxy-8-(3- methyl 2octyl) 5 oxo 2 {l-[3-(4-methylphenyl)- 2 propynyl]} 1,2,3,4 tetrahydro5H [1]benzopyrano [3,4-d1pyridine.

The latter, on reaction with methyl magnesium iodide according to theprocedure described above in Example 1, gives 5 ,5-dimethyl-10-hydroxy-8- 3-methyl-2-octyl) -2'-{ 1- [3 (4methylphenyl)-2-pr0pynyl]}-l,2,3,4-tetrahydro- SH- 1 benzopyrano [3,4-d]pyridine.

We claim: 1. A compound having the formula R2 I N l a I l O==\O Xzwherein X is hydroxy; X is a member of the group consisting of alkylhaving from one to twenty carbon atoms and cycloalkyl-lower-alkylwherein the cycloalkyl moiety contains from three to eight ring carbonatoms; and R is a member of the group consisting ofcycloalkyl-loweralkyl, lower-alkenyl, lower-alkynyl, halo-loWer-alkenyl,phenyl-lower-alkyl, and phenyl-lower-alkynyl, and wherein the benzenering of the phenyl-lower-alkyl and phenylloWer-alkynyl groups areunsubstituted or substituted by from one to three members of the groupconsisting of lower-alkyl, lower-alkoxy, halo, nitro,lower-alkyl-mercapto, methylenedioxy, and trifluoromethyl.

2. A compound according to claim 1 wherein X is hydroxy; X is the sameas in claim 1 and R is an alkyl group having from one to twenty carbonatoms and cycloalkyl-lower-alkyl wherein the cycloalkyl moiety containsthree to eight ring carbon atoms.

3. A compound according to claim 2 wherein R is loWer-alkynyl.

4. IO-hydroxy-S-(3-methyl-2-octyl) -2- l-(2-propynyl) 5-oxo-1,2,3,4tetrahydro-5H-[ 1]benz0pyrano [3,4-d1pyridine according to claim 3wherein R is 3-methy1-2-octyl, and R is 1-(2-propynyl).

References Cited UNITED STATES PATENTS 3,429,889 2/1969 Shulgin 260295ALAN L. ROTMAN, Primary Examiner US. Cl. X.R.

